Cohesinopathies of a Feather Flock Together

Citation: Skibbens RV, Colquhoun JM, Green MJ, Molnar CA, Sin DN, et al. ( Cohesinopathies of a Feather Flock Together Robert V. Skibbens 0 1 2 Jennifer M. Colquhoun 0 1 2 Megan J. Green 0 1 2 Cody A. Molnar 0 1 2 Danielle N. Sin 0 1 2 Brian J. Sullivan 0 1 2 Eden E. Tanzosh 0 1 2 Nancy B. Spinner, University of Pennsylvania, United States of America 0 Current address: Department of Microbiology & Immunology, University of Rochester Medical Center , Rochester, New York , United States of America 1 Funding: RVS is funded by the National Institute of General Medical Sciences (2R15GM083269-02). Neither the funders nor any other sponsor had a role in the preparation of the article 2 1 Department of Biological Sciences, Lehigh University , Bethlehem , Pennsylvania, United States of America , 2 Merck , Sharp & Dohme, West Point, Pennsylvania, United States of America, 3 Janssen R&D, LLC , Raritan, New Jersey , United States of America Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS) are severe developmental maladies that present with nearly an identical suite of multi-spectrum birth defects. Not surprisingly, RBS and CdLS arise from mutations within a single pathway-here involving cohesion. Sister chromatid tethering reactions that comprise cohesion are required for high fidelity chromosome segregation, but cohesin tethers also regulate gene transcription, promote DNA repair, and impact DNA replication. Currently, RBS is thought to arise from elevated levels of apoptosis, mitotic failure, and limited progenitor cell proliferation, while CdLS is thought to arise, instead, from transcription dysregulation. Here, we review new information that implicates RBS gene mutations in altered transcription profiles. We propose that cohesin-dependent transcription dysregulation may extend to other developmental maladies; the diagnoses of which are complicated through multi-functional proteins that manifest a sliding scale of diverse and severe phenotypes. We further review evidence that cohesinopathies are more common than currently posited. - A shared genetic basis of developmental abnormalities Roberts Syndrome/SC-Phocomelia (RBS) and Cornelia de Lange Syndrome (CdLS) are severe multi-spectrum developmental disorders. Patients afflicted with either RBS or CdLS present with nearly identical phenotypes that include acute long-bone growth failure (near-absence of extremities positions hands and/or feet close to the body), mental retardation, craniofacial malformation, and perturbations of heart, kidney, genital, and gastrointestinal development (Table 1). Consistent with this similar suite of phenotypes, both RBS and CdLS arise from mutations within a single pathway. Mutations in ESCO2 produce RBS [13]. ESCO2 is a member of a highly conserved acetyltransferase family (Eco1/ Ctf7 in budding yeast, ESCO2/EFO2 ESCO1/EFO1 in humans) that is essential for sister chromatid tethering reactions (termed cohesion) and high fidelity chromosome segregation [4]. To date, the only known essential substrate of ESCO2 is the cohesin protein SMC3. Cohesin complex (which also contains SMC1A, MCD1/ SCC1/RAD21, and Irr1/Scc3/SA1,2/STAG1,2) binding to DNA requires a deposition complex that contains SCC2/NIPBL and SCC4/MAU2 [4]. Mutations within cohesin subunits (SMC1A, SMC3, and RAD21) and cohesin auxiliary factors (NIPBL, HDAC8, and cohesin-associated PDS5/APRIN) give rise to CdLS [512]. Despite the common manifestations and genetic basis of RBS and CdLS, these developmental abnormalities are thought to arise through different responses to cohesion factor mutations: RBS through elevated levels of apoptosis and limited progenitor cell proliferation, and CdLS through transcription dysregulation. The transcription-based CdLS model is supported by findings that CdLS cells do not exhibit elevated levels of apoptosis or mitotic failure, and that chromatin-bound cohesins not only participate in sister chromatid tethering, but also i) participate in boundary elements that demarcate transcriptional domains, ii) orchestrate DNA promoter and enhancer registration, and iii) associate with transcription regulators (Figure 1). Differentiating between cohesin functions likely depends both on the timing of its enrichment to DNA and post-translational modificationsthe foremost of which appears composed of an acetylation code inscribed by Eco1/Ctf7/ESCO2 [4]. ESCO2 mutations result in elevated frequencies of apoptotic cells Historically, the cataloging of childhood developmental disorders such as RBS was limited to physician-based descriptions. Included in RBS descriptions are cytological observations that included micronuclei, aneuploidy, and chromosomal abnormalities such as heterochromatin repulsion (HR)often referred to as railroad track chromosomes or premature centromere separation (PCS). In humans, RBS arises through loss of both ESCO2 gene copies [13]. ESCO2 knockdown or mutation in model systems (including zebrafish, medaka, and mouse embryos) were found to recapitulate key RBS phenotypes [1315]. In each case, elevated levels of apoptosis were observed in support of a model that mitotic failure induces apoptosis and further limits progenitor cell proliferation. ESCO2 depletion from either mouse neuroepithelium or zebrafish embryos targeted brain and peripheral nervous system cells for death [1315], formally suggesting a mechanism through which cognitive impairment could arise in RBS patients. In contrast, ESCO2 depletion in a medaka model produced increased levels of apoptosis throughout the entire developing embryo [14]. Regardless, apoptotic loss and limited proliferation of progenitor cells remain popular mechanisms through which Craniofacial dysmorphia* Cognitive retardation or decline Organ abnormalities** Skin pigmentation abnormalities Elevated Cancer Incidence Bone marrow/hematopoietic defects Clastogen/genotoxin sensitivity Aneuploidy/Mitotic failure/Apoptosis Partial list of developmental and cytological effects in response to cohesion pathway mutations. *Craniofacial dysmorphia include micrognathia, ear abnormalities, wide-set eyes, beaked or prominent nose, arched eyebrows, or low-set ears. +Limb reductions are often symmetric and involve all four limbs in RBS but predominant in upper extremities in CdLS. Limb reduction appears limited to the radius in NBS and FA. **Organ abnormalities may include renal, urinary, gonadal, gastroesophageal, and others. ++Detection of cryptic HR/PCS may require cell exposure to mitomycin. ND (Not Diagnostic): most studies document that HR/PCS is not elevated in CdLS cells [17,18,20], but see [48]. While HR/PCS is thus not efficacious as a diagnostic tool, numerous chromosomal aberrations are evident in CdLS cells upon exposure to genotoxic agents [20], revealing that CdLS cells may be predispositioned to PCS/HR. Bolded text represents examples of historical cytological diagnostic markers (HR/PCS for RBS, Clastogen sensitivity for FA). Phenotypes shown f (...truncated)